Key Laboratory of Infection and Immunity of Shandong Province & Key Laboratory for Experimental Teratology of Ministry of Education, Shandong University, Jinan, Shandong, 250012, PR China.
Department of Immunology, School of Biomedical Sciences, Shandong University, Jinan, Shandong, 250012, PR China.
Cell Mol Immunol. 2022 Oct;19(10):1141-1152. doi: 10.1038/s41423-022-00917-7. Epub 2022 Sep 1.
Inflammasomes are essential components of the innate immune system and its defense against infections, whereas the dysregulation of inflammasome activation has a detrimental effect on human health. The activation of inflammasomes is subjected to tight regulation to maintain immune homeostasis, yet the underlying mechanism remains elusive. Here, we identify USP3 as a direct deubiquitinating enzyme (DUB) for ASC, the central adapter mediating the assembly and activation of most inflammasomes. USP3 removes the K48-linked ubiquitination on ASC and strengthens its stability by blocking proteasomal degradation. Additionally, USP3 promotes inflammasome activation, and this function was confirmed in mouse models of aluminum (Alum)-induced peritonitis, F. novicida infection and flagellin-induced pneumonia in vivo. Our work unveils that USP3 functions as a key regulator of ASC ubiquitination and maintains the physiological role of ASC in mediating inflammasome activation, and we propose a new mechanism by which the ubiquitination of ASC regulates inflammasome activation.
炎症小体是先天免疫系统的重要组成部分，可抵御感染，而炎症小体的激活失调则对人体健康有害。炎症小体的激活受到严格的调控，以维持免疫平衡，但潜在的机制仍难以捉摸。在这里，我们鉴定 USP3 是 ASC 的一个直接去泛素化酶（DUB），ASC 是介导大多数炎症小体组装和激活的中心衔接蛋白。USP3 去除 ASC 上的 K48 连接泛素化，并通过阻止蛋白酶体降解来增强其稳定性。此外，USP3 促进炎症小体的激活，这一功能在体内铝（Alum）诱导的腹膜炎、F. novicida 感染和鞭毛蛋白诱导的肺炎的小鼠模型中得到了验证。我们的工作揭示了 USP3 作为 ASC 泛素化的关键调节剂，维持 ASC 在介导炎症小体激活中的生理作用，并提出了一种新的机制，即 ASC 的泛素化调节炎症小体的激活。
